International Journal of Molecular Sciences,
Год журнала:
2021,
Номер
22(16), С. 9098 - 9098
Опубликована: Авг. 23, 2021
Protein
kinases
(PKs)
have
been
recognized
as
central
nervous
system
(CNS)-disease-relevant
targets
due
to
their
master
regulatory
role
in
different
signal
transduction
cascades
the
neuroscience
space.
Among
them,
GSK-3β,
FYN,
and
DYRK1A
play
a
crucial
neurodegeneration
context,
deregulation
of
all
three
PKs
has
linked
CNS
disorders
with
unmet
medical
needs,
including
Alzheimer’s
disease
(AD),
Parkinson’s
(PD),
frontotemporal
lobar
degeneration
(FTLD),
several
neuromuscular
disorders.
The
multifactorial
nature
these
diseases,
along
failure
many
advanced
clinical
trials,
lengthy
approval
process
novel
drug
strongly
limited
discovery.
However,
near-decade
from
2010
2020,
computer-assisted
design
strategies
combined
synthetic
efforts
develop
potent
selective
inhibitors
disease-modifying
agents.
In
this
review,
we
described
both
structural
functional
aspects
involvement
crosstalk
pathological
signaling
pathways.
Moreover,
outlined
attractive
medicinal
chemistry
approaches
multi-target
applied
overcome
some
limitations
known
discover
improved
modulators
suitable
blood–brain
barrier
(BBB)
permeability
drug-like
properties.
Molecular Neurodegeneration,
Год журнала:
2020,
Номер
15(1)
Опубликована: Июль 16, 2020
Abstract
Alzheimer’s
disease
(AD)
is
the
most
common
neurodegenerative
disorder
seen
in
age-dependent
dementia.
There
currently
no
effective
treatment
for
AD,
which
may
be
attributed
part
to
lack
of
a
clear
underlying
mechanism.
Studies
within
last
few
decades
provide
growing
evidence
central
role
amyloid
β
(Aβ)
and
tau,
as
well
glial
contributions
various
molecular
cellular
pathways
AD
pathogenesis.
Herein,
we
review
recent
progress
with
respect
Aβ-
tau-associated
mechanisms,
discuss
dysfunction
emphasis
on
neuronal
receptors
that
mediate
Aβ-induced
toxicity.
We
also
other
critical
factors
affect
pathogenesis,
including
genetics,
aging,
variables
related
environment,
lifestyle
habits,
describe
potential
apolipoprotein
E
(APOE),
viral
bacterial
infection,
sleep,
microbiota.
Although
have
gained
much
towards
understanding
aspects
this
devastating
disorder,
greater
commitment
research
mechanism,
diagnostics
will
needed
future
research.
Molecular Neurodegeneration,
Год журнала:
2023,
Номер
18(1)
Опубликована: Июль 3, 2023
Abstract
Stroke
and
late-onset
Alzheimer’s
disease
(AD)
are
risk
factors
for
each
other;
the
comorbidity
of
these
brain
disorders
in
aging
individuals
represents
a
significant
challenge
basic
research
clinical
practice.
The
similarities
differences
between
stroke
AD
terms
pathogenesis
pathophysiology,
however,
have
rarely
been
comparably
reviewed.
Here,
we
discuss
background
recent
progresses
that
important
informative
related
dementia
(ADRD).
Glutamatergic
NMDA
receptor
(NMDAR)
activity
NMDAR-mediated
Ca
2+
influx
essential
neuronal
function
cell
survival.
An
ischemic
insult,
can
cause
rapid
increases
glutamate
concentration
excessive
activation
NMDARs,
leading
to
swift
overload
cells
acute
excitotoxicity
within
hours
days.
On
other
hand,
mild
upregulation
NMDAR
activity,
commonly
seen
animal
models
patients,
is
not
immediately
cytotoxic.
Sustained
hyperactivity
dysregulation
lasting
from
months
years,
nevertheless,
be
pathogenic
slowly
evolving
events,
i.e.
degenerative
excitotoxicity,
development
AD/ADRD.
Specifically,
mediated
by
extrasynaptic
NMDARs
(eNMDARs)
downstream
pathway
transient
potential
cation
channel
subfamily
M
member
(TRPM)
primarily
responsible
excitotoxicity.
subunit
GluN3A
plays
“gatekeeper”
role
neuroprotective
against
both
chronic
Thus,
share
an
NMDAR-
-mediated
mechanism
provides
common
target
preventive
possibly
disease-modifying
therapies.
Memantine
(MEM)
preferentially
blocks
eNMDARs
was
approved
Federal
Drug
Administration
(FDA)
symptomatic
treatment
moderate-to-severe
with
variable
efficacy.
According
eNMDARs,
it
conceivable
MEM
eNMDAR
antagonists
should
administered
much
earlier,
preferably
during
presymptomatic
phases
This
anti-AD
could
simultaneously
serve
as
preconditioning
strategy
attacks
≥
50%
patients.
Future
on
regulation
enduring
control
homeostasis,
events
will
provide
promising
opportunity
understand
treat
AD/ADRD
stroke.
Biomedicines,
Год журнала:
2023,
Номер
11(5), С. 1398 - 1398
Опубликована: Май 8, 2023
Alzheimer’s
disease
(AD)
is
the
most
prominent
neurodegenerative
disorder
in
aging
population.
It
characterized
by
cognitive
decline,
gradual
neurodegeneration,
and
development
of
amyloid-β
(Aβ)-plaques
neurofibrillary
tangles,
which
constitute
hyperphosphorylated
tau.
The
early
stages
neurodegeneration
AD
include
loss
neurons,
followed
synaptic
impairment.
Since
discovery
AD,
substantial
factual
research
has
surfaced
that
outlines
disease’s
causes,
molecular
mechanisms,
prospective
therapeutics,
but
a
successful
cure
for
not
yet
been
discovered.
This
may
be
attributed
to
complicated
pathogenesis
absence
well-defined
mechanism,
constrained
diagnostic
resources
treatment
options.
To
address
aforementioned
challenges,
extensive
modeling
essential
fully
comprehend
underlying
mechanisms
making
it
easier
design
develop
effective
strategies.
Emerging
evidence
over
past
few
decades
supports
critical
role
Aβ
tau
participation
glial
cells
different
cellular
pathways.
review
extensively
discusses
current
understanding
concerning
Aβ-
tau-associated
dysfunction
AD.
Moreover,
risk
factors
associated
with
including
genetics,
aging,
environmental
variables,
lifestyle
habits,
medical
conditions,
viral/bacterial
infections,
psychiatric
have
summarized.
present
study
will
entice
researchers
more
thoroughly
explore
status
mechanism
assist
drug
forthcoming
era.
